Signaling by the TNF-? receptor, TNF-R1, is necessary for the development of inflammation, tissue injury and innate immunity. Recent studies from our laboratory have led to the discovery and characterization of TRUSS (TNF-R1 Ubiquitous Signaling and Scaffolding protein), a ubiquitous and previously unknown protein that serves as a rheostat to augment TNF-R1-induced activation of NF-?B, JNK and apoptosis. To allow assessment of the in vivo function of TRUSS in TNF-R1 signaling we have created mice bearing floxed truss alleles to allow conditional TRUSS deletion. In preliminary studies, we have shown that these mice undergo Cre-mediated recombination at the truss locus resulting in TRUSS deficiency. Our preliminary studies also indicate that TRUSS-/- mice are protected from hepatocyte apoptosis and acute hepatic failure induced by TNF- R1 signaling. Additional studies are now necessary to explore the phenotype of these recently created and validated mice. The goals of this exploratory/developmental R21 application are to: (i) evaluate the consequences of conditional TRUSS deficiency in hepatocytes and endothelial cells on TNF-R1-induced hepatocyte apoptosis and acute hepatitis and (ii) test the hypothesis that TRUSS augments TNF-R1-induced apoptosis through its ability to promote sustained JNK activation. These goals will be addressed by two specific aims. Using global TRUSS-deficient mice, hepatocyte-specific TRUSS deficient mice and endothelial cell-specific TRUSS deficient mice, specific aim 1 will test the hypothesis that hepatocyte apoptosis and acute fatal hepatitis are dependent on TRUSS.
Specific aim 2 will test the hypothesis that the requirement for TRUSS in TNF-R1-induced hepatocyte apoptosis is to promote sustained JNK activation, which in turn activates caspases via the mitochondrial pathway. To our knowledge, the floxed truss mice described in this proposal are unique to our lab. The proposed studies will provide new insights into TRUSS function in vivo and will form the basis of a new R01 application. Recent studies by others have also implicated TRUSS in Alzheimer's disease and breast and lung cancer. Thus, in addition to the goals outlined above, our goal is to make these mice available to others investigators whose work focuses on this understudied gene.
TNF-?plays a key role in inflammation and innate immunity (e.g. sepsis, acute hepatitis and rheumatoid arthritis). The work in this application will provide new insights into how TNF-?, operating through a molecule called TRUSS, initiates and regulates these disorders. Understanding the role of TRUSS in TNF-?-induced response may provide a new target for treating these disorders.